Haem oxygenase 1 gene induction by glucose deprivation is mediated by reactive oxygen species via the mitochondrial electron-transport chain
Haem oxygenase 1 gene induction by glucose deprivation is mediated by reactive oxygen species via the mitochondrial electron-transport chain
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DOI：
10.1042/bj20021731
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发表时间：
2003-05-01
影响因子：
4.1
通讯作者：
Agarwal, A
中科院分区：
文献类型：
--
作者：
Chang, SH;Garcia, J;Agarwal, A
葡萄糖消耗导致细胞应激和活性氧（ROS）产生，这引起适应性和保护性反应。一种这样的保护性反应是血红素加氧酶I（HO-1）的诱导，其催化血红素降解中的限速步骤，释放铁、CO和胆绿素。本研究评价了ROS和线粒体电子传递链在葡萄糖剥夺诱导HepG 2肝癌细胞HO-1表达中的作用。无论是N-乙酰半胱氨酸，抗氧化剂，或去铁胺，铁螯合剂，导致在葡萄糖剥夺过程中HO-1 mRNA和蛋白诱导的剂量依赖性抑制，这表明氧化还原和铁依赖性机制。电子传递链复合物111的抑制剂、抗霉素A和Myxothiazol、ATP合酶抑制剂寡霉素和用2-脱氧葡萄糖或葡糖胺消耗ATP也阻断HO-1诱导。为了进一步说明ROS的参与，特别是H2 O2，我们发现过氧化氢酶的过表达完全阻断了葡萄糖剥夺对HO-1的激活。相反，抑制核因子κ B、丝裂原活化蛋白激酶（MAPK）、蛋白激酶A、蛋白激酶C、磷酸肌醇3-激酶、环加氧酶或胞浆磷脂酶A（2），不能阻止HO-1的诱导。这些结果表明，HO-1基因的激活葡萄糖剥夺介导的“葡萄糖代谢反应”途径通过产生ROS，该途径需要一个功能性的电子传递链。
Glucose depletion results in cellular stress and reactive oxygen species (ROS) production, which evokes adaptive and protective responses. One such protective response is the induction of haem oxygenase I (HO-1), which catalyses the rate-limiting step in haem degradation, liberating iron, CO and biliverdin. The present study evaluated the role of ROS and the mitochondrial electron-transport chain in the induction of HO-1 by glucose deprivation in HepG2 hepatoma cells. Either N-acetylcysteine, an antioxidant, or deferoxamine, an iron chelator, resulted in a dose-dependent inhibition of HO-1 mRNA and protein induction during glucose deprivation, suggesting a redox- and iron-dependent mechanism. Inhibitors of electron-transport chain complex 111, antimycin A and myxothiazol, the ATP synthase inhibitor oligomycin and ATP depletion with 2-deoxyglucose or glucosamine also blocked HO-1 induction. To address the involvement of ROS further, specifically H2O2, we showed that overexpression of catalase completely blocked HO-1 activation by glucose deprivation. In contrast, inhibition of nuclear factor kappaB, mitogen-activated protein kinase (MAPK), protein kinase A, protein kinase C, phosphoinositide 3-kinase, cyclo-oxygenase or cytosolic phospholipase A(2), did not prevent HO-1 induction. These results demonstrate that activation of the HO-1 gene by glucose deprivation is mediated by a 'glucose metabolic response' pathway via generation of ROS and that the pathway requires a functional electron-transport chain.